1. Field of the Invention
This application discloses inventions that relate generally and in various embodiments to transdermal patches useful for delivering various medicaments to patients in need thereof.
2. Description of the Background
Transdermal drug delivery systems have become an increasingly important means of administering medicaments to patients. Such systems offer advantages over other modes of administration such as, for example, introduction through ingestion via the gastro-intestinal tract or through injections.
Transdermal patches generally include a reservoir comprised of a hydrogel containing the medicament. Hydrogels are formed from very long molecular chain polymers that are crosslinked, and contain water. Such crosslinked water soluble polymers may be used as effective reservoirs as they provide a comfortable and conformable interface with the skin, as well as excellent biocompatibility. Additional hydrogels may also be used to promote healing in wound dressings. See U.S. Pat. No. 5,578,661, which is hereby incorporated by reference.
Hydrogels used in the pharmaceutical industry generally come in two basic forms—amorphous gel and sheet gel. While amorphous gels are useful as lotions to spread on the skin, transdermal patches typically employ sheet gels in their formulation and construction. To formulate a hydrogel as a sheet, some form of chemical crosslinking is typically employed. Crosslinking is essentially a process by which the polymers that make up the hydrogel are covalently crosslinked to one another, thereby providing physical structure to the gel.
Common methods of crosslinking include UV-induced crosslinking and chemical crosslinking. By mixing the polymeric hydrogel composition with specific chemical crosslinking agents, crosslinks between the polymers are formed. The chemical crosslinking agent remains in the hydrogel and, as such, the crosslinking process continues to occur at a slow rate during the storage of the transdermal patch depending on ambient temperature, humidity, or other environmental factors. Furthermore, the chemical crosslinking agent that remains in the transdermal patch may chemically interfere either directly or with the absorption into the skin of certain active agents, thereby attenuating the effectiveness of the transdermal patch. With UV-induced crosslinking, the crosslinking is achieved by controlled exposure to UV light without the use of chemicals. UV-induced crosslinking may also continue after the initial treatment with UV light through subsequent exposure of the transdermal patch to sunlight. Thus, for both chemical and UV-induced crosslinking, the art has encountered difficulties in achieving precise control of the crosslinking process and thus the generation of a consistent transdermal product.
In contrast to chemical or UV-induced crosslinking, crosslinking through electron beam or ionized beam radiation provides numerous benefits. Such techniques are disclosed in U.S. Pat. No. 4,684,558, which is hereby incorporated by reference. Ionized beam crosslinking occurs when the hydrogel is exposed to an accelerated, high-energy beam of electrons, thereby causing crosslinking among the polymeric strands. The first benefit is that ionized beam crosslinked hydrogels possess an improved purity of formulation, given no additional chemical components need to be added, as in chemical crosslinking. Furthermore, because the crosslinking occurs only when the gel is exposed to the high-energy electron beam, the ability to reproducibly generate patches having the same characteristics is dramatically improved.
The use of electron beam or ionized beam radiation in crosslinking may, however, generate a complication for drug-containing hydrogels. Commonly, an unformed reservoir is incorporated with a biologically active agent (i.e., a drug) before the ionization or curing process begins. This drastically limits the choice of drug to only those that are stable during the crosslinking process. The high-energy particles may degrade the drug and the products of that degradation reaction can interfere with both the crosslinking reaction as well as the efficacy of the formulation.
To avoid these concerns, some procedures in the prior art allow the patient to add a separate drug-containing phase to a transdermal patch at the time of use. This process is not only cumbersome for the patient, but also gives rise to significant issues of compliance and formulation variability. The prior art does not provide an effective manner for generating a drug-containing crosslinked hydrogel transdermal formulations that avoids these complications.
Hydrogels that are able to be crosslinked through irradiation may be formulated from a diversity of compounds. Those include the water-soluble polymers include irradiated crosslinked polyethylene oxide (PEO), polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), polyacrylamide, and polyethylene glycol (PEG). The crosslinked water soluble polymer sheet by nature of its preparation by irradiation crosslinking is of low bioburden and is non-toxic, non-irritating and non-sensitizing to the skin. This is particularly assured by the fact that no chemical crosslinking agents or organic solvents are required to synthesize the crosslinked water soluble polymer material.
While these physical characteristics of ionized beam crosslinked hydrogel sheets are known in the prior art, the impact that these factors may have on transdermal patch performance have yet to be investigated.
Additionally, transdermal formulations are often augmented by various compounds to improve either physical or physiological properties, though it is unknown how such compounds impact the bioavailability or stability of biologically active components in a crosslinked hydrogel. One such additive is transcutol, also known as 2-(2-ethyoxethoxy)ethanol, carbitol, carbitol cellosolve, dioxitol, poly-solv DE, and dowanal DE; (hereinafter “transcutol”). Transcutol is a clear, colorless, hygroscopic liquid and is commonly used as an industrial solvent. As a solvent, it is able to transfer various polar and non-polar medicaments (i.e., drugs) into a solid or semisolid substrate for administration to patients. The use of transcutol as a skin penetration enhancer is known, though the impact it may have on drug-containing hydrogel stability and delivery of drugs from a hydrogel transdermal patch is unexplored. See U.S. Pat. No. 5,460,620, which is hereby incorporated by reference.